Amidoxime derivatives

ABSTRACT

Novel amidoxime derivatives having the following structural formula (IV) of (IV&#39;): ##STR1## wherein R 1  represents methyl or ethyl group and R 2  represents hydrogen or methyl group, useful as a raw material for 3-amino-5-methyl isoxazole, are prepared from β-amino crotonitrile. Said isoxazole, useful as an intermediate for various medicines, may be prepared without producing any by-products of isomer.

The present invention relates to a novel amidoxime and a method forpreparing the same. The amidoxime of the present invention is a usefulraw material for 3-amino-5-methyl isoxazole which is an intermediate forvarious medicines such as sulfonamide. Therefore, the present inventionalso relates to a novel and useful method for preparing the abovementioned isoxazole.

We tried to prepare 3-amino-5-methyl isoxazole by usingacetoacetonitrile as the starting material. In case of that the startingmaterial was reacted with hydroxylamine without any chemical protectionof carbonyl group of the starting material, hydroxylamine ispreferentially reacted with carbonyl group rather than nitrile group andtherefore the objective compound was little prepared. Then, we tried thereaction by using the starting material having carbonyl group previouslyprotected. Even in this case we were not able to obtain the objectivesubstance.

However, we have eagerly researched this reaction and found that thepreparative substance of this reaction is an amidoxime derivative whichis a novel compound, not having written in any literatures, in whichhydroxylamine is attached to nitrile group. Furthermore, we have foundthat the novel amidoxime derivatives can be easily and selectivelyconverted to 3-amino-5-methyl isoxazole by treating in an acidiccondition. It is a surprising fact that the yield of isomer, namely5-amino-3-methyl isoxazole, is not substantially recognized, as comparedwith the fact that the known similar reactions always give relativelylarge amounts of isomers.

Accordingly, an object of the present invention is to provide novelamidoxime derivatives.

An other object of the present invention is to provide a method forpreparing the same.

A further object of the present invention is to provide an effectivemethod for preparing 3-amino-5-methyl isoxazole, which is useful as anintermediate for various medicaments and the like.

The method according to the present invention is shown as the followingequations. ##STR2## As shown above, according to the present invention,β-aminocrotonitrile (namely diacetonitrile) (I) is hydrolyzed to produceacetoacetonitrile (II), the obtained compound (II) is reacted withtrialkyl orthoformate or ethyleneglycol derivatives in the presence ofan acid catalyst to produce β-dialkoxy acetoacetonitrile (III) orβ-ethylenedioxy acetoacetonitrile derivatives(III'), or ethylenedioxybutyramide is dehydrated using a dehydrating agent to produceβ-ethylenedioxy acetoacetonitrile derivatives(III'), the obtained (III)or (III') is reacted with hydroxylamine in the presence of an alkalinesubstance to produce β-dialkoxy aceto-acetamidoxime (IV) orβ-ethylenedioxy acetoacetamidoxime derivatives(IV') and the obtainedcompound (IV) or (IV') is treated in an acidic condition to be convertedto 3-amino-5-methyl isoxazole.

The novel amidoxime derivatives thus obtained are colorless, transparentand viscous liquids or white crystals.

The methods according to the present invention are preferably conductedas follows. The hydrolysis of β-aminocrotonitrile is, first of all,carried out in an aqueous solution in an acidic condition ofhydrochloric acid at 50°-100° C. for 1-5 hours. More preferably, thehydrolysis is conducted at 80° C. for a period of 2 hours, and, aftercompletion of the reaction, the product is extracted with ethyl acetateand then vacuum-distilled to obtain acetoacetonitrile. Although it hasbeen previously known that acetoacetonitrile is much polymerizable, wehave found that it is stable under a weak acidic condition and can bestored for a long period of time. Then, acetoacetonitrile and trialkylorthoformate or ethyleneglycol derivatives are reacted in the presenceof an acid catalyst to produce ketal compound of acetoacetonitrile. Asthe trialkyl orthoformate, trimethyl orthoformate and triethylorthoformate are preferably used, and as the ethyleneglycol derivativesethyleneglycol and propyleneglycol are preferably used owing to theiravailability. Among them, ethyleneglycol is the best. As the acidcatalyst, mineral acids and sulfonic acids such as hydrochloric acid,hydrogen chloride, sulfuric acid, benzene-sulfonic acid andp-toluene-sulfonic acid are preferably used. As the reaction medium,lower alcohols and aromatic hydrocarbons, such as methanol, ethanol,benzen, toluene and xylene, are preferably used. The reactiontemperature and the reaction time are not limited. However when usingtrialkyl orthoformate, the reaction is preferably conducted at aboutroom temperature for a few hours, and when using ethyleneglycolderivatives, the reaction is preferably conducted at the boiling pointof a solvent used as the reaction medium while water is removedazeotropically. Usually, the reaction is finished in a few hours. Aftercompletion of the reaction, according to conventional method, thesolvent is distilled out and then the objective compound, namely ketalcompound of acetoacetonitrile is obtained by vacuum distillation.β-Ethylenedioxy acetoacetonitrile derivatives are also prepared byreacting β-ethylenedioxy butyramide with phosphorus pentaoxide in thepresence of triethyl amine. In this reaction, a reaction solvent is notnecessarily used but preferably used in order to proceed smoothly thereaction. As the solvent, inert organic solvents, such as benzene, arepreferably used. The reaction is preferably conducted at a temperatureof from about room temperature to about 100° C., the solvent isdistilled out after completion of the reaction and then β-ethylenedioxyacetoacetonitrile is obtained by vacuum distillation.

Ketal of acetoacetonitrile thus obtained is reacted with hydroxylaminein the presence of an alkaline substance to produce a novel compound,ketal of acetoacetamidoxime. As the alkaline substance to be used inthis reaction, alkali metal hydroxides and alkali metal alkoxides arepreferably used. Among them, sodium hydroxide and sodium methylate aremore preferably used owing to their availability. As the reactionsolvent to be used in this reaction, various solvents such as loweralcohols, water and mixtures thereof may be used. Among them, methanol,water and mixture thereof are more preferably used. The reactiontemperature and the reaction time are not necessarily limited, but-10°-100° C. and a few--ten or more hours are usually preferable. Theamount of the alkaline substance is preferably 1-4 moles to 1 mole ofketal of acetoacetonitrile and the amount of hydroxylamine is preferably1-3 moles thereto. After completion of the reaction, distilling out ofthe solvent, extraction by ethyl acetate and distilling out of ethylacetate are conducted and the residue obtained thereafter contains agreat part of the objective compound, ketal of acetoacetamidoxime. Thecompound thus obtained can be distilled or recrystallized but can bedirectly used in the next reaction without any purification.

Ketal of acetoacetamidoxime thus obtained is subjected to ring-closingreaction using an acid catalyst. As the acid catalyst to be used in thisreaction, mineral acids, especially hydrochloric acid, are preferablyused. As the reaction solvent to be used in this reaction, loweralcohol, water and mixture thereof are preferably used. The reaction ispreferably conducted at about room temperature -100° C. for a few hours.After completion of the reaction, 3-amino-5-methyl isoxazole can beobtained in accordance with conventional methods. In this case, one ofthe greatest features of the present invention is the fact that uselessisomer, 5-amino-3-methyl isoxazole, is not be substantially produced.

Conventional methods for preparing 3-amino-5-methyl isoxazole are, forexample,

(a) a method in which propiolonitrile derivatives are reacted withhydroxylamine in the presence of alkali metal hydroxide (Japanese PatentPublication No. 42-23191),

(b) a method in which halogen-carbonitrile is reacted with hydroxylamineor hydroxylamine having protected amino group in an alkaline medium(Japanese Patent Publication No. 41-21147), and

(c) a method in which alkyl ester of acylpyruvic acid is converted to5-alkyl-3-carboalkoxy isoxazole, its amide and then its amine (JapanesePatent Publication No. 37-17231, 37-4886, 37-4887). In case of (a), thestarting material is not available and the yield of the objectivecompound is low, and in case of (b) and (c), a large amount of isomerssuch as 5-amino-3-methyl isoxazole is necessarily produced. They havesuch disadvantages as using expensive derivative of hydroxylamine andcontrolling strictly the reaction condition in order to prevent theyield of the isomer.

However, the present invention shows such great advantages thatby-production of isomer, 5-amino-3-methyl isoxazole, is not accompaniedat all and 3-amino-5-methyl isoxazole is selectively obtained with highyield.

Moreover, β-aminocrotonitrile, the starting material, is a compoundeasily manufactured as compared with acetonitrile, one of the typicalpetrochemical goods, and therefore, the present invention shows suchadvantage that an inexpensive and easily available compound is used asthe starting material.

Moreover, the present invention shows such advantage that the novelcompounds, amidoxime derivatives, can be converted easily to3-amino-5-methyl isoxazole which is an essential compound for preparinguseful sulfametoxazole, one of durable sulfonamides. Hereinafter, thepresent invention is explained by Examples.

EXAMPLE 1

41 grams of β-aminocrotonitrile were dissolved in a mixture of 50cc ofwater and 50cc of concentrated hydrochloric acid and reacted at 80° C.for 2 hours.

After cooling, the precipitate was filtered and extracted with ethylacetate followed by distilling out of the solvent and vacuumdistillation, and 34.5 grams of acetoacetonitrile of colorlesstransparent liquid (bp 73°-75° C./6mm Hg) were obtained. (Yield 84.15%)

EXAMPLE 2

34.5 grams of acetoacetonitrile were dissolved in 100ml of methanol, 66grams of methyl orthoformate and 10 drops of concentrated sulfuric acidwere added thereto and stirred for a night. After completion of thereaction, 0.5 grams of potassium carbonate was added thereto and stirredfor 30 minutes to neutralize. Methanol was distilled out by means of anevaporator and 48.5 grams of β-dimethoxy acetoacetonitrile of colorlesstransparent liquid (bp 58°-60° C./7mm Hg) were obtained. (Yield 90.3%)

EXAMPLE 3

16 grams of acetoacetonitrile were dissolved in 50cc of ethanol, and 42grams of ethyl orthoformate and 5 drops of sulfuric acid were addedthereto. After completion of the reaction, 0.5 grams of potassiumcarbonate was added thereto and stirred for 30 minutes to neutralize.

Ethanol was distilled out by means of evaporator and 22 grams ofβ-diethoxy acetoacetonitrile of colorless transparent liquid wereobtained by vacuum distillation (bp 48°-50° C./4.5mm Hg). (Yield 72.6%)

EXAMPLE 4

33.2 grams of acetoacetonitrile were dissolved in 200ml of benzene, 28grams of ethylene glycol and 0.2 gram of para-toluene sulfonic acid wereadded thereto and water produced through the reaction was distilled outwith benzene. The terminal point of the reaction was checked by theamount of water distilled out. The remaining benzene was distilled outby means of an evaporator and 47.7 grams of β-ethylenedioxyacetoacetonitrile of colorless transparent liquid were obtained byvacuum distillation. (bp 63°-66° C./7mm Hg) (Yield 93.9%)

EXAMPLE 5

Using 63 grams of acetoacetonitrile, 60 grams of propylene glycol, 200mlof toluene and 0.2 gram of paratoluene sulfonic acid, the same procedureas shown in Example 4 was conducted and 104 grams of β-propylenedioxyacetoacetonitrile of colorless transparent liquid were obtained. (bp70°-75° C./6mm Hg) (Yield 96.3%)

EXAMPLE 6

103 grams of β-ethylenedioxy butyramide were dissolved in a mixture of250ml of benzene and 145 grams of triethyl amine, and 13.5 grams ofphosphorus pentaoxide were gradually added thereto. The temperature wasgradually elevated to reflux for 1 hour, and benzene and triethyl aminewere recovered. The residue was vacuum-distilled and 79.4 grams ofβ-ethylenedioxy acetoacetonitrile were obtained. (Yield 87.4%)

EXAMPLE 7

Into 50ml of water 10 grams of sodium hydroxide were dissolved, thenafter addition of 50ml of methanol, 13.5 grams of hydroxylaminehydrochloride were dissolved under an ice-cooled condition. Finally 12.9grams of β-dimethoxy acetoacetonitrile were dropped thereto and stirredfor one night at a room temperature. After reflux for 2 hours as apost-reaction, the product was extracted with ethyl acetate and 11 gramsof β-dimethoxy acetoacetamidoxime of colorless, transparent and viscousliquid were obtained therefrom. (bp 104°-114° C./7mm Hg) (Yield 67.9%)

    ______________________________________                                        Elemental Analysis                                                                      C.sub.6 H.sub.14 O.sub.3 N.sub.2                                              C        H          N                                               ______________________________________                                        calcd.      44.4 %     8.6 %      173. %                                      found       45.16 %    8.49 %     17.03 %                                     ______________________________________                                    

EXAMPLE 8

Using 10 grams of sodium hydroxide, 100 ml of water, 100ml of methanol,27 grams of hydroxylamine hydrochloride and 31.5 grams of β-diethoxyacetoacetonitrile, the procedure shown in Example 7 was repeated, then20.5 grams of β-diethoxy acetoacetamidoxime of white needle crystal wereobtained. (mp 111° C.) (Yield 54%)

    ______________________________________                                        Elemental Analysis                                                                      C.sub.8 H.sub.18 O.sub.3 N.sub.2                                              C        H          N                                               ______________________________________                                        calcd.      50.5  %    9.5  %     14.7  %                                     found       50.43 %    9.69 %     14.73 %                                     ______________________________________                                    

EXAMPLE 9

Using 50 grams of sodium hydroxide, 250 ml of water, 250ml of methanol,67.5 grams of hydroxylamine hydrochloride and 55 grams ofβ-ethylenedioxy acetoacetonitrile, the procedure shown in Example 7 wasconducted and 51.8 grams of β-ethylenedioxy acetoacetamidoxime wereobtained after recrystallization. (mp 71° C.) (Yield 74.5%)

    ______________________________________                                        Elemental Analysis                                                                      C.sub.6 H.sub.12 O.sub.3 N.sub.2                                              C        H          N                                               ______________________________________                                        calcd.      45.0  %    7.5  %     17.5  %                                     found       45.02 %    7.54 %     17.35 %                                     ______________________________________                                    

EXAMPLE 10

Using 60 grams of sodium hydroxide, 300 ml of water, 300ml of methanol,70 grams of hydroxylamine hydrochloride and 71 grams of β-propylenedioxyacetoacetonitrile, the procedure shown in Example 7 was conducted and65.6 grams of β-propylenedioxy acetoacetamidoxime of colorless,transparent, viscous liquid were obtained by vacuum distillation. (bp131°-136° C./7mm Hg) (Yield 75%)

    ______________________________________                                        Elemental Analysis                                                                      C.sub.7 H.sub.14 O.sub.3 N.sub.2                                              C        H          N                                               ______________________________________                                        calcd.      48.3  %    8.0  %     16.1  %                                     found       48.32 %    8.02 %     16.22 %                                     ______________________________________                                    

EXAMPLE 11

Using 10 grams of sodium hydroxide, 100 ml of water, 13.5 grams ofhydroxylamine hydrochloride and 12.9 grams of β-dimethoxyacetoacetonitrile but no methanol, the procedure shown in Example 7 wasconducted for 89 hours. The solvent was distilled out and the residuewas vacuum distilled and 5.2 grams of β-dimethoxy acetoacetamidoxime ofcolorless, transparent and viscous liquid were obtained. (bp 111° C./7mmHg) (Yield 60.5%)

EXAMPLE 12

Into 100ml of ethanol 11.2 grams of sodium methylate were dissolved andmethanol solution containing 10.4 grams of hydroxylamine hydrochloridewere dropped thereto under an ice-cooled condition and 13 grams ofβ-dimethoxy aceto-acetonitrile were dropped thereto, followed by theprocedure shown in Example 7, and 11.9 grams of β-dimethoxyacetoacetamidoxime of colorless, transparent and viscous liquid wereobtained. (Yield 56.0%)

EXAMPLE 13

Into 100ml of ethanol, metal sodium was dissolved, methanol solutioncontaining 15 grams of hydroxylamine hydrochloride was added theretounder an ice-cooled condition and 22 grams of β-diethoxyacetoacetonitrile were dropped thereto, followed by the same procedureas shown in Example 7, 16 grams of β-diethoxy acetoacetamidoxime ofwhite solid were obtained. (mp 111° C.) (Yield 60%)

EXAMPLE 14

Into 100ml of butanol 4.6 grams of metal sodium were dissolved, methanolsolution containing 10.4 grams of hydroxylamine hydrochloride weredropped thereto under an ice-cooled condition and 13 grams ofβ-dimethoxy acetoacetonitrile were added thereto, followed by the sameprocedure as shown in Example 7, 10.1 grams of β-dimethoxyacetoacetamidoxime of colorless, transparent and viscous liquid wereobtained by vacuum distillation. (Yield 60%)

EXAMPLE 15

Into 20ml of ethanol 3.2 grams of β-dimethoxy aceto-acetamidoxime weredissolved and a few drops of concentrated hydrochloric acid was addedthereto and stirred for 2 hours and left as it was for one night. Theproduct was extracted with ethyl acetate and 1.9 grams of3-amino-5-methyl isoxazole of pale yellow solid was obtained therefrom.(Yield 96.9%)

EXAMPLE 16

Into 100ml of ethanol 9 grams of β-diethoxy acetoacetamidoxime weredissolved and the same procedure shown in Example 15 was conducted. 4grams of 3-amino-5-methyl isoxazole were obtained. (Yield 85.2%)

EXAMPLE 17

Using 16 grams of β-ethylenedioxy acetoacetamidoxime and 100ml ofethanol, the same procedure as shown in Example 15 was conducted, and5.9 grams of 3-amino-5-methyl isoxazole were obtained. (Yield 60%)

EXAMPLE 18

Using 17.5 grams of β-propylenedioxy acetoacetamidoxime and 100ml ofethanol, the same procedure as shown in Example 15 was conducted, and12.2 grams of 3-amino-5-methyl isoxazole were obtained. (Yield 80%)

APPLICATION EXAMPLE

Onto 7 grams of pyridine 4 grams of 3-amino-5-methyl isoxazole aboveobtained were added and heated to 40° C. p-Acetylaminobenzene sulfonylchloride was added thereto in 6 times in a total amount of 10.5 gramswhile maintaining the temperature between 40° C. and 50° C. After addingthe total amount of 10.5 grams of p-acetylamino benzen sulfonylchloride, the liquid temperature is elevated to 65°-70° C., and thereaction was carried out for 3 hours.

Thereafter, 30ml of hot water of more than 60° C. were added thereto and60°-65° C. was kept for 30 minutes and then cooled to below 40° C. Thenthe pH thereof was adjusted to 3.6 by adding 30% H₂ SO₄ and the productwas filtered, washed and dried to obtain 11 grams of3-p-acetyl-amino-benzene-sulfonamide-5-methyl isoxazole.

11 grams of the acetyl compound thus obtained were added into NaOHaqueous solution (NaOH 4 grams, water 32 grams) and heated for 1 hour.After cooling, the pH of the reaction solution was adjusted to 5 todeposit white crystal. 8.0 grams of the pure product (mp 167.6°-168.2°C.) were obtained by recrystallization from alcohol. The IR and TLCvalues of the product was completely identical with the standard sample.(Yield 75.8%)

What is claimed is:
 1. Amidoxim derivatives having the formula ##STR3##wherein R₁ is methyl group or ethyl group and R₂ is hydrogen or methylgroup.